Project Summary/Abstract Venous thromboembolism (VTE), which includes both deep vein thrombosis and pulmonary embolism, annually affects between 350,000 and 600,000 Americans and results in more than 100,000 deaths. This makes VTE the third leading cause of cardiovascular mortality, behind heart attack and stroke. Treatment of VTE events is best evaluated from the perspective of 3 phases: acute (first 5-10 days), primary treatment (first 6 months post-event) and secondary prevention (?6 months post-event). Traditionally VTE was treated acutely in-hospital, and warfarin was used for primary treatment and secondary prevention. Recently there have been two major advances in the treatment of VTE: 1) the outpatient treatment of VTE in the acute phase, and 2) the approval in 2012 of direct oral anticoagulants (DOACs) for VTE primary treatment and secondary prevention. Randomized trials have demonstrated that outpatient VTE management and DOACs (i.e. dabigatran, rivaroxaban, apixaban, edoxaban) are at least as effective as their traditional alternatives. However, randomized trials are not always generalizable to the usual clinical setting, and are typically underpowered to identify subgroups most at risk for adverse outcomes. Moreover, safety concerns have been raised for DOACs. As such, additional research is needed to determine, relative to their traditional alternatives, the effectiveness of these new treatment strategies, their risks, and to identify patient subgroups more likely to experience benefit or harm. Comparative effectiveness research can address these questions in ?real-world? settings. Using data from two large U.S. commercial claims databases, Optum and MarketScan, which include more than 500,000 patients with VTE, we propose to evaluate risks and benefits associated with inpatient vs. outpatient management in the acute phase, DOACs versus warfarin for the primary treatment of VTE, and DOACs versus warfarin versus no anticoagulant therapy for VTE secondary prevention. Primary outcomes include recurrent VTE, intracranial hemorrhage, and mortality. We will also identify patient subgroups, defined by age, sex, race/ethnicity, comorbidities, use of other medications, and index VTE presentation (unprovoked, provoked non-cancer, cancer-related) for which DOACs are particularly beneficial or hazardous. Additionally, we will develop the first risk prediction models for VTE recurrence, intracranial hemorrhage and mortality which incorporate DOACs. These predictive models will have a direct and immediate impact on clinical practice, helping clinicians and patients make decisions about the most appropriate anticoagulant therapy. NHLBI has listed anticoagulant therapies as a top priority for comparative effectiveness research. In sum, findings from this research would immediately impact clinical practice, reinforcing or leading to reconsideration of the existing clinical guidelines for VTE management. Further, in harmony with the 2015 Precision Medicine Initiative, this research would directly inform tailored treatment strategies, thereby optimizing patient outcomes.